Significant progress was made in the last reporting period, resulting in seven publications. We identified a a potent mu-agonist delta-antagonist, and an exceedingly potent antinociceptive in the enantiomeric C9-Substituted 5-(3-Hydroxyphenyl)-N-phenylethylmorphan series. Another study reported the synthesis and pharmacological effects of the enantiomers of the N-phenethyl analogues of the ortho and para e- and f-oxide-bridged phenylmorphans. Further progress was made in the structure-activity of salvinorin A analogs, including exploration of the 1-position. Importantly, we reported herkinorin analogues with differential beta-arrestin-2 interactions. As described in that study:[unreadable] [unreadable] "Salvinorin A is a psychoactive natural product that has been found to be a potent and selective kappa opioid receptor agonist in vitro and in vivo. The activity of salvinorin A is unusual compared to other opioids such as morphine in that it mediates potent kappa opioid receptor signaling yet leads to less receptor down-regulation than observed with other kappa agonists. Our initial chemical modifications of salvinorin A have yielded one analogue, herkinorin ( 1c), with high affinity at the mu-OR. We recently reported that 1c does not promote the recruitment of beta-arrestin-2 to the mu-OR or receptor internalization. Here we describe three new derivatives of 1c ( 3c, 3f, and 3i) with similar properties and one, benzamide 7b, that promotes recruitment of beta-arrestin-2 to the mu-OR and receptor internalization. When the important role mu opioid receptor regulation plays in determining physiological responsiveness to opioid narcotics is considered, mu opioids derived from salvinorin A may offer a unique template for the development of functionally selective mu opioid receptor-ligands with the ability to produce analgesia while limiting adverse side effects.